tbuckley/cabot-search huggingface dataset:
Abstract 627: Custom Vectra® Polaris™ fluorescent multiplex IHC panel identifies mature tertiary lymphoid structures in colorectal cancer
Authors: Sara G. Pollan, Arezoo Hanifi, James Hargrove, Erinn A. Parnell, Jessica Lin, Josette William Ragheb, Qingyan Au
Journal: Cancer Research (2022)

Abstract Introduction: Tertiary lymphoid structures (TLS) are promising prognostic indicators of positive outcomes for patients with solid tumors including colorectal cancer (CRC) [1]. Large-scale retrospective analysis shows patients with mature TLS in particular respond to PD-1/PD-L1 antibody treatment with improved objective response, progression-free and overall survival [2]. Since not all patients respond to PD-1/PD-L1 antibody treatment, identifying patients with mature TLS is clinically relevant as it enables selection of patients likely to respond to immune checkpoint blockade. Mature TLS are composed of T cells (CD3+), follicular B cells (CD20+), germinal center B cells (CD23+), and follicular dendritic cells (CD21+) [3]. The ability to identify and evaluate TLS is limited by detection methods which traditionally employ hematoxylin and eosin (H&amp;E) staining for visual quantification of immune aggregates, potentially significantly underestimating their quantity [4]. Multiplexed fluorescent immunohistochemistry (IHC) detection assays have the capability to precisely quantify mature TLS within the TME. Colorectal cancer specimens expressing a dynamic range of TLS are stained with a novel custom Vectra® Polaris™ multiplex immunofluorescence panel detecting CD20, CD21, CD23, CD3 and pan-cytokeratin. Identification of mature TLS with CD3+CD20+CD21+ and CD3+CD20+CD23+ expression in the TME is reported. Results: Vectra® Polaris™ TLS multiplex immunofluorescence panel successfully identified mature TLS in the TME of colorectal cancer patient samples. TLS were quantified via custom analytics algorithms generated with Indica HALO software. Conclusion: Characteristics of TME immunity in colorectal cancer differentially impact an individual patient’s odds of survival [5]. The novel Vectra® Polaris™ multiplex assay in this study shows a detailed picture of mature TLS in patient cancer samples. Future applications of this panel include investigations of TLS associated with successful anti-tumor immune development and therapeutic response to treatment. [1] Oncoimmunology. 2020; 9(1): 1724763 [2] Nat Cancer. 2, 794-802 (2021) [3] Oncoimmunology. 2021; 10(1): 1900508. [4] Mod Pathol 2017 Sep;30(9):1204-1212. doi: 10.1038/modpathol.2017.43. [5] Cell. 2020 Sep 3;182(5):1341-1359.e19. doi: 10.1016/j.cell.2020.07.005 Citation Format: Sara G. Pollan, Arezoo Hanifi, James Hargrove, Erinn A. Parnell, Jessica Lin, Josette William Ragheb, Qingyan Au. Custom Vectra® Polaris™ fluorescent multiplex IHC panel identifies mature tertiary lymphoid structures in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 627.
Abstract 419: The development of BRPF1 degraders as a potential treatment for acute myeloid leukemia
Authors: Daniel Joseph Glynn, Rosie Crampton, Thomas Pesnot, Andrew Scott, Anne-Chloe Nassoy, Ralph Kirk, Daniele Narducci, Gary Nelson, Lynette Ongiri, Habiba Begum, Vincent Rao, Matilda Bingham, Rhoanne McPherson, Darryl Turner
Journal: Cancer Research (2022)

Abstract Acetylation of histones and additional nuclear proteins is a key mechanism in the regulation of gene expression. Aberrant acetylation has been linked to a wide range of diseases including cancer, inflammation, and neurodevelopmental disorders. Histone acetylation is introduced by histone acetyltransferases complexes (HATs), where substrate specificity is dramatically enhanced by scaffolding proteins that activate and target them to specific chromatin sites. A protein of interest with both epigenetic acetyl reader and scaffolding function is the protein Bromodomain and PHD finger-containing protein 1 (BRPF1). The Protein contains domains of two plant homeodomain (PHD) fingers separated by a zinc knuckle (PZP domain), a bromodomain, and a proline-tryptophan-tryptophan-proline (PWWP) Tudor domain. Native BRPF1 complexes can contain either MOZ/MORF or HBO1 as the catalytic MYST-family acetyltransferase subunit and the stable complex with Moz-Tif2 is known to lead to the development of human acute myeloid leukemia (AML). Given this, we chose to pursue the development of BRPF1 degraders to probe cancer disease biology especially in AML, where new therapies are required to overcome several unmet needs such as less-toxic treatments and relapsed/refractory disease paradigms. Here we present the design and synthesis of a range of BRPF1 degraders in highly desirable physicochemical space utilizing in-silico modeling. The prepared degraders which utilize multiple E3 ligases were then screened against cell lines harboring Mixed-lineage leukemia (MLL) translocations specifically the THP-1 cell line. In addition to this, we investigated the ability of the compounds to effectively degrade the target and suitability of our degraders for potential in-vivo exposure through a panel of routine ADMET assays. Citation Format: Daniel Joseph Glynn, Rosie Crampton, Thomas Pesnot, Andrew Scott, Anne-Chloe Nassoy, Ralph Kirk, Daniele Narducci, Gary Nelson, Lynette Ongiri, Habiba Begum, Vincent Rao, Matilda Bingham, Rhoanne McPherson, Darryl Turner. The development of BRPF1 degraders as a potential treatment for acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 419.
Abstract 2394: Discovery of a sex-specific metabolic phenotype in KRAS mutant colorectal cancer
Authors: Hong Yan, Yuping Cai, Xinyi Shen, Abhishek Jain, Philip B Paty, Marcus Bosenberg, Sajid A Khan, Caroline Johnson
Journal: Cancer Research (2022)

Abstract KRAS mutations occur in 35-45% of all colorectal cancer (CRC) cases and are notoriously difficult to treat. It is known that anomalous metabolism is a hallmark for cancer, however the relationship between mutant KRAS and tumor metabolism in CRCs has not been fully explored. We recently showed sex-disparities in metabolism by primary tumor location, indicating the pressing need to investigate the role of biological sex in CRC. Our aim was therefore to determine whether mutant KRAS alters metabolism in a sex-specific manner. We performed non-targeted metabolomics and targeted metabolomics on stage I-III chemotherapy-naive KRAS-mutant and wild type CRC patient tumor tissues (n=197) using ultra-high-performance liquid chromatography (UHPLC) coupled to quadrupole Time-of-Flight Mass Spectrometry (QTOF-MS), and tandem MS (MS/MS). Our results showed that tumors from male patients were cystine(cysteine)-dependent, with altered glutathione (GSH) biosynthesis, transsulfuration activity, methionine metabolism, utilization of lipoxygenase pathways. Simultaneously, we performed comprehensive bioinformatic analysis of gene expression data from the Gene Expression Omnibus to further validate mutant KRAS effects on CRCs by sex. Our findings demonstrated differential expression to CBS, GPX4, GSS, ACSL4, ATF4, FTH1 and EGPR genes that are all involved in regulation of these metabolic pathways and indicate a role for ferroptosis. This data therefore validated our findings of decreased transsulfuration activity (regulated by CBS) and decreased GSH biosynthesis (regulated by GSS) in male patients; this finding was not seen in female patients. To further examine differences in ferroptosis by sex, it was seen that GPX4 was differentially expressed between KRAS mutant and wild type (p&amp;lt;0.05) in males, but not in females. Meanwhile, ACSL4, which appears to be a predictive marker for ferroptosis sensitivity, showed upregulated expression in males with mutant KRAS (p&amp;lt;0.00001). Further, KRAS mutant type linked to a poor 5-year overall survival only in male using Kaplan-Meier survival analysis. This is the first report to show unique sex-specific metabolic signatures by KRAS status in CRC patients indicating a role of decreased ferroptosis in males, thus a novel avenue for therapeutic approaches. Citation Format: Hong Yan, Yuping Cai, Xinyi Shen, Abhishek Jain, Philip B Paty, Marcus Bosenberg, Sajid A Khan, Caroline Johnson. Discovery of a sex-specific metabolic phenotype in KRAS mutant colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2394.
Abstract 6034: Characterization of a novel syngeneic cSCC mouse model to advance immunotherapy treatments
Authors: Alanis Enid Rodriguez Rosario, Roberto Rangel, Jeffrey Myers
Journal: Cancer Research (2022)

Abstract Cutaneous Squamous Cell Carcinoma (cSCC) is the second most common malignancy diagnosed in Caucasians with an incidence of about one million cases per year. TP53 and p16 are the most common mutated genes in cSCC. Previous studies of cSCC have shown that patients with both p53 and p16 mutations have lower survival rates. There are currently no syngeneic mouse preclinical models to accelerate the efficacy of immunotherapy combinations to treat cSCC. Our laboratory has generated several genetically engineered mouse models (GEMMs) containing tissue-specific p53 and p16 gene mutations. Recently, we have immortalized three murine cSCC cell lines (cSCC-5690, cSCC-8006, and cSCC-8271) derived from spontaneous skin tumors from GEMMs. Therefore, we hypothesized that the double mutant cell line cSCC-5690 enhances cell survival, tumor aggressiveness, and has lower sensitivity to antibody immunotherapy. Protein and RNA expression of the cell lines were validated by western blotting and qRT-PCR assays. Sphere and soft agar assays were used to evaluate the stem cell population and tumorigenicity of the cell lines. Then, we examined the chemosensitivity with cisplatin through clonogenic assays. To further study the tumorigenicity of cells, we evaluated in vivo tumor growth on C57BL/6J immunocompetent mice by injecting subcutaneously the tumor cell lines. The three cell lines expressed different levels of keratin 14 (K14), but cSCC 5690 and 8006 expressed high levels of genes related to oncogenic pathways as well as mesenchymal markers. The cell line cSCC-5690 expressing mutant p53 R172H with p16 gene deletion, showed an enhanced sphere, and colony tumor formation and both tumorigenic cell lines (cSCC-5690, 8006) showed different sensitivities to cisplatin treatment. A higher tumor growth rate was observed with cSCC-5690 compared to cSCC-8006, while cSCC-8271 showed no tumor growth. Immunohistochemistry studies demonstrated that both cSCC-5690 and 8006 tumors expressed vimentin but only cSCC-5690 expressed K14. The most aggressive syngeneic tumor model (cSCC-5690) was used to evaluate the anti-tumor efficiency of anti-PD1, anti-CD47 antibodies, and STING-agonist. Preliminary results revealed a significant tumor response only to STING agonist (c-di-GMP) which activates the innate and adaptive immune response. Therefore, we were able to characterize all three cell lines and established a new mouse model of cSCC as a relevant platform for immunotherapy studies. Citation Format: Alanis Enid Rodriguez Rosario, Roberto Rangel, Jeffrey Myers. Characterization of a novel syngeneic cSCC mouse model to advance immunotherapy treatments [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6034.
Abstract 5559: Development of a novel PD-L1xCD40 bispecific antibody with excellent efficacy and safety profile for cancer therapy
Authors: Haishan luo, Zihong Meng, Jimmy Rong, Yuandong Wang, Yunxing Yang, Fei Chen, Youhong Wang, Victor Chen, Gang Deng, Yebo He, Xin Gan, Yiping Rong
Journal: Cancer Research (2022)

Abstract CD40 agonistic antibody is emerging as a front-line immunotherapy for patients with cancer. However, despite its remarkable curative effects, serious immune-related adverse reactions limit the clinical application of CD40 agonists. Crosslinking-dependent activation is one of the promising approaches to diminish the adverse effects of CD40 agonists. Agonistic CD40 stimulation on antigen presenting cells (APCs) not only promotes activation of T cells, but also results in PD-L1 upregulation on APCs, thus creating a negative feedback loop to dampen the anti-tumor immune response. Therefore, we hypothesized that the combination of CD40 agonist and blockade of PD-1/PD-L1 interaction may further induce a synergistic effect on T cell activation and anti-tumor activity. Here, we report a novel PD-L1xCD40 Bispecific Antibody (BsAb) designed to have synergistic curative effects as well as improved safety profiles. The PD-L1/CD40 BsAb was generated using the Harbour HBICE࣪® platform. It exhibited superior binding activities to both PD-L1 and CD40, respectively. CD40 activation was fully relied on the PD-L1 crosslinking. The PD-L1xCD40 BsAb showed potent tumor growth inhibition in preclinical efficacy models. Meanwhile, it showed much improved safety profile compared to a reference anti-CD40 agonistic antibody in the preclinical tox models. Overall, the PD-L1xCD40 BsAb demonstrated remarkable in vivo anti-tumor efficacy and improved safety profiles in preclinical models, which presents it as a promising candidate for the development of next-generation cancer immune therapeutics. Citation Format: Haishan luo, Zihong Meng, Jimmy Rong, Yuandong Wang, Yunxing Yang, Fei Chen, Youhong Wang, Victor Chen, Gang Deng, Yebo He, Xin Gan, Yiping Rong. Development of a novel PD-L1xCD40 bispecific antibody with excellent efficacy and safety profile for cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5559.
Abstract 5628: Immune repertoire sequencing facilitates gamma delta T cell clonal determination
Authors: Chen Song, Ariel Erijman, Bradley W. Langhorst, Pingfang Liu, Eileen T. Dimalanta, Theodore B. Davis
Journal: Cancer Research (2022)

Abstract Gamma-delta T cells are a small fraction of T lymphocytes with only 1-5% of the overall T cell population, but they are an important subset that have unique contributions to both innate and adaptive immunity. Gamma-delta T cells can recognize a broad range of antigens to provide rapid responses to pathogens, and can also interact with both immune cells and non-immune tissue cells triggering regulatory and cytotoxic responses. These unique features make them ideal candidates that could be targeted to induce durable immunity in the context of different pathologies. There has been growing interest in understanding the contributions of gamma-delta T cells to immunology and developing efficient gamma-delta T-cell-based therapies for cancer, infectious disease, and autoimmune disease. In this study, we have implemented T cell repertoire sequencing for high throughput characterization. Gamma-delta T cells were enriched from tissues and peripheral blood mononuclear cells (PBMCs). RNA was extracted and used to generate full length TCR libraries. Unique molecular identifiers (UMIs) were incorporated to discretely barcode each mRNA molecule, enabling absolute quantitative ranking of TCR clone abundance. Full length immune repertoire sequencing facilitates the detection of distinct and shared clones in tissue and blood samples, enabling the identification of disease specific clones to evaluate immunotherapy effects. In addition, RNA sequencing was performed for gene expression analysis of gamma-delta T cells to identify cell phenotypes. Citation Format: Chen Song, Ariel Erijman, Bradley W. Langhorst, Pingfang Liu, Eileen T. Dimalanta, Theodore B. Davis. Immune repertoire sequencing facilitates gamma delta T cell clonal determination [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5628.
Abstract 4208: <i>In situ</i> vaccination of non-small cell lung cancer with CXCL9/10-engineered dendritic cells combined with PD-1 blockade
Authors: Raymond J. Lim, Ramin Salehi-rad, Linh M. Tran, Camelia Dumitras, Jensen W. Abascal, William P. Crosson, Tejas S. Patel, Samantha Man, Rui Li, Kostyantyn Krysan, Bin Liu, Steven M. Dubinett
Journal: Cancer Research (2022)

Abstract Lung cancer is the most common cause of cancer death worldwide with approximately 85% of patients having non-small cell lung cancer (NSCLC). Checkpoint blockade immunotherapy has evolved the current treatment landscape with robust and durable responses in approximately 20% of patients with progressive, locally advanced or metastatic NSCLC, as well as in treatment-naïve advanced disease. Inefficient tumor antigen presentation, diminished T cell infiltration into tumor and LKB1-inactivating mutations contribute to the mechanisms of resistance to programmed death-ligand 1 (PD-L1) or programmed cell death protein 1 (PD-1) blockade in NSCLC. LKB1 deficiency also facilitates an immunosuppressive environment that promotes tumor growth. One approach to overcome this immunosuppressive tumor microenvironment (TME) is to utilize in situ vaccination with gene-modified functional antigen presenting cells (APCs) to enhance tumor antigen presentation and promote tumor-specific T cell activation. It has been shown that the chemokines CXCL9 and CXCL10 (CXCL9/10) are important signaling molecules secreted by CD103+ dendritic cells (DCs) to orchestrate the anti-tumor immunity. Thus, we hypothesize that intratumoral (IT) injection of CXCL9/10-secreting DCs (CXCL9/10-DCs) can potentiate the response to anti-PD-1 monotherapy in LKB1-deficient NSCLC by promoting antigen presentation and inducing T cell infiltration. Our preliminary data shows that CXCL9/10-DC injection modulates systemic immunity and generates anti-tumor responses that are augmented by the combination treatment with anti-PD1. In an in vivo murine model of Lkb1-null lung cancer bearing high tumor mutational burden (TMB), CXCL9/10-DC facilitates recruitment of effector T cells into the TME and tumor-specific T cell activation. These studies will enhance our understanding of anti-tumor immunity mediated by in situ DC vaccination and facilitate the improvement of novel vaccine therapies. B. Liu and S. M. Dubinett contributed equally to this work. Citation Format: Raymond J. Lim, Ramin Salehi-rad, Linh M. Tran, Camelia Dumitras, Jensen W. Abascal, William P. Crosson, Tejas S. Patel, Samantha Man, Rui Li, Kostyantyn Krysan, Bin Liu, Steven M. Dubinett. In situ vaccination of non-small cell lung cancer with CXCL9/10-engineered dendritic cells combined with PD-1 blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4208.
Abstract 5843: Truncated APC &amp; AXIN2 expression contribute to maintaining β-catenin/WNT signaling at the “Just Right” level for CRC cell proliferation
Authors: Chi Zhang, Caroline O. Facey, Katherine Funk, Lynn M. Opdenaker, Bruce M. Boman
Journal: Cancer Research (2022)

Abstract Adenomatous polyposis coli (APC) mutation leads to increased WNT signaling and stem cell overpopulation, which drives development of colorectal cancer (CRC). APC mutations often encode a truncated protein that has loss of APC’s domains that mediate APC interaction with AXIN2. A substantial body of scientific evidence indicates that truncated APC is essential for CRC cell proliferation by maintaining beta-catenin levels and WNT signaling at the “just right” level (known as the “Just Right” Hypothesis). Thus, AXIN2 is of particular interest because both wild-type APC and AXIN2 are part of the beta-catenin destruction complex, which is essential for tumor-suppressing ability. Hypothesis: the degree of AXIN2 expression, in the context of truncated APC, is critical to maintain WNT-signaling activity at the “just right” level which is optimal for CRC cell proliferation. Accordingly, we evaluated the effect of AXIN2 levels in CRC cells that contain APC protein-truncating mutations on WNT signaling (Top Flash assay), expression of WNT-targeted genes, and CRC cell proliferation and differentiation. We found that modulating AXIN2 expression altered WNT signaling, expression of WNT-targeted genes, and CRC cell proliferation in CRC cell lines with different APC-truncation causing mutations. Indeed, western blot results showed that knock down of AXIN2 gene expression increased truncated-APC and AXIN1 protein expression, and decreased expression of several WNT-target genes (e.g. LGR5, CD44, c-Jun, c-Myc, Cyclin D1), particularly genes that have reported roles in cell cycle regulation. These findings were consistent with our independent bioinformatics analyses of NCI TCGA RNA-seq data on CRC patients. Overall, our study suggests that i) The beta-catenin destruction complex is still functional at a certain level despite APC-truncating mutations; ii) Perturbing AXIN2 expression leads to changes in WNT-signaling activity that deviate from a level that is “just right” for malignant cell proliferation, likely by affecting the function of the destruction complex; iii) Deviation from “just right” WNT signaling levels alters WNT-target gene expression and diminishes the ability of APC-mutant CRC cells to maintain uncontrolled proliferation. Citation Format: Chi Zhang, Caroline O. Facey, Katherine Funk, Lynn M. Opdenaker, Bruce M. Boman. Truncated APC &amp; AXIN2 expression contribute to maintaining β-catenin/WNT signaling at the “Just Right” level for CRC cell proliferation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5843.
Atlas of currently available human neutralizing antibodies against SARS-CoV-2 and escape by Omicron sub-variants BA.1/BA.1.1/BA.2/BA.3
Authors: Min Huang, Lili Wu, Anqi Zheng, Yufeng Xie, Qingwen He, Xiaoyu Rong, Pu Han, Pei Du, Pengcheng Han, Zengyuan Zhang, Runchu Zhao, Yunfei Jia, Linjie Li, Bin Bai, Ziliang Hu, Shixiong Hu, Sheng Niu, Yu Hu, Honghui Liu, Bo Liu, Kaige Cui, Weiwei Li, Xin Zhao, Kefang Liu, Jianxun Qi, Qihui Wang, George Fu Gao
Journal: Immunity (2022)

SARS-CoV-2 Omicron variant has presented significant challenges to current antibodies and vaccines. Herein, we systematically compared the efficacy of 50 human monoclonal antibodies (mAbs), covering the seven identified epitope classes of the SARS-CoV-2 RBD, against Omicron sub-variants BA.1, BA.1.1, BA.2, and BA.3. Binding and pseudovirus-based neutralizing assays revealed that 37 of the 50 mAbs lost neutralizing activities, whereas the others displayed variably decreased activities against the four Omicron sub-variants. BA.2 was found to be more sensitive to RBD-5 antibodies than the other sub-variants. Furthermore, a quaternary complex structure of BA.1 RBD with three mAbs showing different neutralizing potencies against Omicron provided a basis for understanding the immune evasion of Omicron sub-variants and revealed the lack of G446S mutation accounting for the sensitivity of BA.2 to RBD-5 mAbs. Our results may guide the application of the available mAbs and facilitate the development of universal therapeutic antibodies and vaccines against COVID-19.